Primary Drying: The Sublimation of Ice - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 109

shelf space, such practice may seem to be uneconomical, but as regards
product quality and drying time, it is to be preferred over excessive fill
depths.
The effect of fill depth can best be demonstrated by considering the
resistance of the dried cake to further sublimation. Figure 3 illustrates the
effect of cake thickness (fill volume) on the resistance to sublimation for a
series of products with the same solid content, 5% w/w. The linear
relationship between fill depth and resistance suggests the absence of a
concentration gradient within the frozen solution, i.e. an indicator of
good freeze-drying practice. The reason for the markedly greater slope for
mannitol has not been explained; it might be due to the possibility that
mannitol had crystallised during the process. None of the lines passes
through the origin, indicating that not too much significance can be
attached to the actual numerical values. Nevertheless, the relationship
between fill depth and plug resistance to sublimation is demonstrated.

8.7 Ideal Conditions

A set of parameters now emerges, the correct combination of which
would produce ideal conditions, at least from the point of view of freeze-
drying. This combination would offer an efficient drying cycle producing
a high yield of dried product with an acceptable storage stability. Unfor-
tunately, the frequently used device to maintain a high sublimation rate is
just to heat the shelf, but this practice is to be discouraged. It may well
cause the product temperature at the bottom of a vial to rise to above T g .
Preferably the shelf temperature should be set to its maximum calculated
value at the beginning of the drying cycle, and to be reduced gradually, to
arrive back at T g on completion of ice removal. Such a protocol may
however be difficult to implement in practice because the site of cooling,
the ice front, is remote from the site of heating, i.e. the vial base.
It is thus established that moderate concentrations and fill depths
facilitate ice sublimation. To arrive at a reasonable compromise, a solid
content in the region of 10% w/w should be aimed at. Coupled with a fill
depth of ca. 5 mm, this provides a good compromise to achieve an
efficient primary drying protocol for many pharmaceutical formulations.

8.8 Accelerated Freeze-Drying

In efforts to speed up ice sublimation, the use of a variety of additives
has been proposed. For example, tertiary butyl alcohol (TBA) has been
claimed to accelerate the primary drying rate, partly because of its high